Arthritis and other rheumatologic disorders are among the most common human health afflictions. In the United States, they are more prevalent and a more common cause of disability than either heart disease or cancer (Lawrence et al., J. Rheumatol., 16:427–41 (1989)). Epidemiological surveys estimate that over 40 million people in this country alone are afflicted with arthritis, accounting for some 315 million physician visits per year (Yelin and Felts, Arthritis Rheum., 33:750–5 (1990)). The economic cost that arthritis extracts on the nation is equally enormous—over $100 billion per year in medical costs and lost productivity (Yelin and Callahan, Arthritis Rheum., 38:1351–62 (1995)). With a demographic of an aging population, the health and economic tolls of arthritis and other musculoskeletal disorders are predicted to increase even more dramatically in the years to come.
Arthritis, which literally means “inflammation of the joint,” is a broad clinical term that is used to describe an array of rheumatologic conditions that commonly present with pain, swelling, and stiffness in the joints that may progress to deformity and loss of mobility in severe cases. Based on various clinical, radiologic, and laboratory criteria, clinicians have further divided arthritic disorders into different types. The most common type of arthritis is Osteoarthritis (OA) (Lawrence, J., Rheumatisms in populations, London: William Heinemann Medical Books, (1977)). OA affects people of all ages and ethnicities, with a peak prevalence of 80% among people over 65 (Moskowitz, R. W., Am. J. Med., 83:5–10 (1987)). Joints commonly involved include the hips, knees, and finger joints of the hand as well as the weight-bearing joints in the vertebral column. Cardinal features of OA include chondrocyte hyperplasia and necrosis, cartilage destruction, osteophyte and bony, cyst formation, joint space narrowing, and the presence of debris in the joint space that may ultimately lead to the formation of a synovial pannus that bridges the entire joint, rendering it immobile. Although its name implies a central role for inflammation in its pathogenesis, the inflammatory process is not prominent in most cases of OA and may be present in some cases as a secondary phenomenon of joint destruction.
Besides OA, other common types of arthritis include crystal arthropathies, rheumatoid arthritis, spondyloarthropathies, infectious arthritis, and others. Each of these types of arthritis is characterized by a set of clinical and pathological features (e.g. mineral deposits in crystal arthropathies, chronic inflammation and autoimmune reactions in rheumatoid arthritis, etc.), though these features may not necessarily be specific to a particular subtype of arthritis. For example, the mineral deposits in affected joints in crystal arthropathies are often found in other forms of arthritis such as OA. The high prevalence of crystal deposits and synovial fluid crystals in patients presenting with symptoms of OA suggests that crystal deposition may be a causal or contributing factor to the clinical entity normally termed OA (Huskisson et al., Ann. Rheum. Dis., 38:423–8 (1979); Ledingham et al., Ann. Rheum. Dis., 52:520–6 (1993); Gerster, J. C., J Rheumatol., 21:2164–5 (1994); Fam, A. G., Curr. Opin. Rheumatol, 7:364–8 (1995)).
Despite the tremendous individual and social impact of arthritis, very little is currently known about the underlying etiology of these disorders. While twin and family studies have identified a strong hereditary component for many arthritic disorders, other studies have also reported links to weight, occupation, presence of prior joint injuries as well as other metabolic and endocrine diseases (Klippel and Dieppe, Rheumatology (2nd Ed.), London: Mosby, (1998)). This poor understanding of arthritic diseases is reflected in the limited therapy options available for arthritic patients today. The mainstay in anti-arthritic therapy today consists of the clinical management of symptoms with pain medication, dietary supplements, and exercise. Unfortunately none of these treatments are very effective in slowing the progression of the disease, and patients that are in advanced stages of the disease often require joint replacement and bone fusion surgeries (Klippel and Dieppe, supra).
A spontaneous mouse mutation called progressive ankylosis (ank) was described several years ago that causes abnormal calcium deposition in many skeletal elements, enlargement and fusion of many small bones, and new bone and cartilage formation that bridges all synovial joints in the skeleton (Sweet and Green, J Hered., 72:87–93 (1981)). Mice homozygous for the mutation show progressive loss of mobility that begins in the distal limbs, and later spreads to include many joints in the limbs, sternum, and vertebral column. Histological, EM, and X-ray diffraction studies suggest that the earliest changes in the animals are increased depositions of calcium hydroxyapatite in bones, cartilage, and synovial joints, leading to wider and thicker bones (Hakim et al., Arthritis Rheum., 27:1411–20 (1984); Sampson, H. W., Am. J Anat., 182:257–69 (1988); Sampson, H. W., Spine, 13:645–9 (1988); Mahowald et al., J. Rheumatol., 16:60–6 (1989); Sampson et al., Acta Anat. (Basel), 141:36–41 (1991)). Increased mineral levels in joints are thought to trigger proliferative changes in the synovium and ectopic formation of cartilage and bone in and around joints (Hakim et al., Arthritis Rheum., 29:114–23 (1986)).
The ank mouse mutation provides an important model system for studying genetic predisposition to ectopic mineral deposition and arthritis in humans. Several human joint syndromes are known that show clear autosomal inheritance and a clinical presentation of joint pain, chondrocalcinosis, osteoarthritis, or pseudo rheumatoid arthritis, often requiring hip or knee replacements of affected individuals in their twenties or thirties (Baldwin et al., Am. J. Hum. Genet., 56:692–7 (1995); Hughes et al., Hum. Mol. Genet., 4:1225–8 (1995); Andrew et al., Am. J. Hum. Genet., 64:136–45 (1999)). Like the ank mutation, these human syndromes are associated with increased mineral deposition in bone and cartilage elements. In addition, 30% or more of the elderly human population show increased deposition of mineral in cartilage and bone elements (Felson et al., J Rheumatol., 16:1241–5 (1989)). Increased mineral deposition doubles the risk of developing osteoarthritis, which is one of the major causes of morbidity and decreased activity and a major reason for consulting doctors and taking medications in both young and elderly populations (Felson et al., J Rheumatol., 16:1241–5 (1989); Badley et al., J Rheumatol, 21:505–14 (1994)).
Although the ank mutation was first reported in 1981, nothing is known about the molecular nature of the ank gene product. Isolation of this gene will lead to important new understanding of the mechanisms that control mineral deposition, osteophyte formation, and genetic susceptibility to osteoarthritis in both mice and humans. In addition, identification of the normal product of the gene may suggest new treatments or drug targets that can be used to modulate levels of mineral deposition and osteoarthritis in millions of human patients.
There is a need for the identification and determination of a gene associated with arthritis. Identification of such a gene will allow advances in the diagnosis, prognosis, and therapy of arthritis.